PROTEOSTASIS: NOVEL INSIGHTS AND TECHNOLOGIES

Abstract Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity and reduce neuroinflammation in the aging CNS. We derived cTFEB;HSA-Cre transgenic mice in the P301S MAPT background and we detected a significant reduction in hyperphosphorylated tau[AT8 phospho-tau antibody] in whole hippocampal lysates and in the dentate gyrus of cTFEB;HSACre;P301S mice compared to their single transgenic P301S littermate controls. Nanostring nCounter®AD panel analysis reveals displayed reductions in microglia activation modules in P301S MAPT/cTFEB:HSACre hippocampi, suggesting reduced neuroinflammation. We also determined that these CNS benefit sin P301S MAPT/cTFEB:HSACre mice were accompanied by activation of exercise-associated neurotrophic signaling and reduced markers of advancing tau-associated pathologies in the hippocampus. These provocative results suggest that enhanced skeletal muscle proteostasis modifies the accumulation of pathogenic tau isoforms and reduces neuroinflammation in the CNS of P301S MAPT mice via activation of exercise-associated signaling in the CNS.

with case-based evidence from a pilot RCT of an electronic tablet communication application provisioned to mechanically ventilated ICU patients, and efforts toward hospital-wide implementation. Recent literature on patient communication technology consists primarily of qualitative, descriptive accounts of video communication (i.e., ICU visits) or provision of augmentative and alternative communication.
Recommendations for required skills, standardization, and research regarding patient communication technology are provided.

PROTEOSTASIS: NOVEL INSIGHTS AND TECHNOLOGIES
Chair: Andrew Pickering

GENETIC AND PHARMACOLOGIC PROTEASOME AUGMENTATION AMELIORATES ALZHEIMER'S-LIKE PATHOLOGY IN MICE AND FLIES Andrew Pickering, University of Alabama at Birmingham, Birmingham, Alabama, United States
The proteasome has key roles in neuronal proteostasis, including removal of misfolded and oxidized proteins, presynaptic protein turnover, as well as synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer's disease (AD) (1-3). Artificial impairment of proteasome function can mimic many neurodegenerative phenotypes (4, 5). We report impaired proteasome function to represent an early-stage marker of AD preceding many other markers of the disease. Significantly, we show that prevention of proteasome dysfunction by genetic manipulation in fly and cell culture models of AD delays mortality, cell death, and cognitive deficits. We developed a transgenic mouse with neuronal-specific proteasome overexpression which, when crossed with a mouse model of AD showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of novel TAT-based proteasome-activating peptidomimetics. These agonists stably penetrate the blood-brain-barrier and enhance 20S as well as 26S proteasome activity. We show that treatment with these agonists protects against cell death in a cell culture model of AD as well as both cognitive decline and mortality in fly and mouse models of AD. The protective effects observed from proteasome overexpression in our models appear to be driven at least in part by increased turnover of the amyloid precursor protein (APP) by the proteasome. We conclude that the proteasome plays an important role in AD progression. Furthermore, augmentation of proteasome function is protective against AD-like pathogenesis in diverse models of the disease, representing a new therapeutic target for treatment of AD.

PROTEOSTASIS: NOVEL INSIGHTS AND TECHNOLOGIES Constanza Cortes, University of Alabama at Birmingham, Birmingham, Alabama, United States
Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and Innovation in Aging, 2022, Vol. 6, No. S1 aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity and reduce neuroinflammation in the aging CNS. We derived cTFEB;HSA-Cre transgenic mice in the P301S MAPT background and we detected a significant reduction in hyperphosphorylated tau[AT8 phospho-tau antibody] in whole hippocampal lysates and in the dentate gyrus of cTFEB;HSACre;P301S mice compared to their single transgenic P301S littermate controls. Nanostring nCounter®AD panel analysis reveals displayed reductions in microglia activation modules in P301S MAPT/cTFEB:HSACre hippocampi, suggesting reduced neuroinflammation. We also determined that these CNS benefit sin P301S MAPT/cTFEB:HSACre mice were accompanied by activation of exercise-associated neurotrophic signaling and reduced markers of advancing tau-associated pathologies in the hippocampus. These provocative results suggest that enhanced skeletal muscle proteostasis modifies the accumulation of pathogenic tau isoforms and reduces neuroinflammation in the CNS of P301S MAPT mice via activation of exercise-associated signaling in the CNS. Rahul Samant, Babraham Institute, Cambridge, England, United Kingdom Loss of protein homeostasis ('proteostasis') and onset of cellular senescence are two conserved hallmarks of ageing. Healthy proteostasis relies on tightly-regulated intracellular quality control circuits that co-ordinate clearance of potentially toxic misfolded proteins arising from various internal or external stresses throughout an organism's lifespan. Proteostasis imbalances are mechanistically linked to a broad range of ageing-associated diseases, and are also characteristic of cellular senescence-a permanent cell cycle arrest that prevents uncontrolled proliferation during development, injury repair, and tumorigenesis, but drives ageing-associated frailty, degeneration, and therapy resistance. Across a range of replicative and stressinduced senescence models in primary human cells, we have discovered differences in how misfolded proteins are triaged when compared with proliferating, quiescent, or immortalised cells-especially at the level of ubiquitin-mediated protein clearance systems. Given recent findings that proteostasis modulators act as senolytics with geroprotective properties, our work highlights the need for an improved fundamental understanding of how different ageing hallmarks are inter-connected in order to drive advances in human healthspan.